1. Recognition, Diagnosis, and Management of Neuroendocrine Tumors
James C. Yao, MD
Associate Professor and Deputy Chair, Gastrointestinal Medical Oncology
University of Texas M. D. Anderson Cancer Center

2. Learning Objectives
After completing this activity, participants should be able to:
Outline patient signs and symptoms that should lead to an evaluation for NETs
Describe the diagnostic work-up that can confirm a suspected diagnosis of NET
Review current treatment approaches for NETs and expected patient outcomes
Analyze recent clinical trial data demonstrating improved outcomes beyond symptom control in patients with advanced NETs
Bullet 2:  ... confirm a suspected diagnosis of NET (delete s)?
NET = neuroendocrine tumor

3. NETs: A Not-So-Rare Disease
Epidemiology
Signs and symptoms of NETs

4. Incidence of NETs Increasing
6.00
600
All malignant neoplasms
5.00
500
4.00
400
Incidence per 100,000 - NETs
3.00
Incidence per 100,000 – All malignant neoplasms
300
2.00
200
TO PURCHASE – USE AS IS
1.00
100
Neuroendocrine tumors
0.00
1973
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2004
Yao JC et al. J Clin Oncol. 2008;26: 4 4

5. NETs Are Second Most Prevalent Gastrointestinal Tumor
NET Prevalence in the US, 2004
1200
Median survival (1988 – 2004)
Localized 203 months
Regional 114 months
Distant 39 months
103,312 cases (35/100,000)
1100
Cases (thousands)
100
RE-CREATE AS IS
Note: the break in the colon cancer bar is correct, as it indicates a change in the scale used in the Y axis (because colon cancer is more common than the others by an order of magnitude
Colon
Neuroendocrine
Stomach
Pancreas
Esophagus
Hepatobiliary
29-year limited duration prevalence analysis based on SEER.
Yao JC et al. J Clin Oncol. 2008;26:
SEER = Surveillance, Epidemiology, and End Results 5 5 5

6. Autopsy Studies Carcinoid1,2 Islet cell3 2 studies 0.7% to 1.2%
> 15,000 cases each
0.7% to 1.2%
Islet cell3
> 11,000 cases from Hong Kong
0.1%
1. Berge T, Linell F. Acta Pathol Microbiol Scand. 1976;84:
2. Moertel CG et al. Cancer. 1961;14:
3. Lam KY, Lo CY. Eur J Surg Oncol. 1997;23:36-42.

7. NETs Are Often Diagnosed Late
Vague abdominal symptoms
Death
Diarrhea
Flushing
Metastases
RE-CREATE AS IS
Primary tumor
Time
Vinik A, Moattari AR. Dig Dis Sci. 1989;34[Suppl]:14S-27S.

8. Missed Symptoms and Late Diagnosis
Flushing
No sweating
First sip of alcohol
Diarrhea
Especially nocturnal
Wheezing
Irritable bowel syndrome
Bloating
Keep as is
50% + 24% + 27% = 101% OK? [copyeditor note]
Yes—these numbers are rounded from the original publication; keep as is.[SD note]
Yao JC et al. J Clin Oncol. 2008;26:

9. Diagnosis and Initial Work-Up
Pathologic confirmation
Assess disease burden
Assess functional status

10. Anatomic Imaging: CT Std Arterial Venous Delayed
Imaging studies property of James Yao, MD CT: computed tomography.

11. Anatomic Imaging: MRI MRI = magnetic resonance imaging
Imaging studies property of James Yao, MD.

12. Anatomic CT and Indium-111 Pentetreotide Scintigraphy
Imaging studies property of James Yao, MD.

13. Tumor Markers General NET markers
Chromogranin A
Affected by somatostatin analogues, proton pump inhibitors, kidney function, liver function
Neuron-specific enolase
Midgut (small bowel, appendix, cecum)
5 HIAA (24-hr urine collection)
Serotonin (blood, more variable)
5-HIAA = 5-hydroxyindoleacetic acid

14. Other Markers in Functional Tumors
Fasting measurements when possible
Gastrinoma
Gastrin
Glucagonoma
Glucagon
Insulinoma
Insulin
Pro-insulin
C-peptide
VIPoma
Vasoactive intestinal peptide

15. Principles of Marker Assessment
Lots of markers; expression can change over time
Chromogranin B and C, pancreastatin, substance P, neurotensin, neurokinin A, pancreatic polypeptide
Take large panel of markers at key points
Diagnosis or relapse
Follow a few elevated markers over time
Not necessary to check every marker at each visit

16. Current Treatment Approaches
Somatostatin analogs
Chemotherapy for pancreatic NETs
Regional therapy approaches

17. Limited Options for Advanced NETs
Functional
Octreotide LAR + chemotherapy
pNET
Hepatic artery embolization
Investigational
agents
(No approved therapies
available)
Nonfunctional
Chemotherapy
Carcinoid syndrome
Octreotide LAR
Disease progression
Midgut No syndrome
Carcinoid
No standard
RE-CREATE as is
Non-midgut No syndrome
No standard
LAR = long-acting release; pNET = pancreatic NET

18. pNET: Streptozocin-Based Chemotherapy
Imaging studies property of James Yao, MD.

19. Need for Tumor Control Agents Remains High
Survival Patients with distant NET ( )
Limited Options
Carcinoid
No approved drugs for tumor control
pNET
Streptozocin approved but perceived to be toxic
No agreed-upon standard treatment for tumor control
Carcinoid
Pancreatic NET
IMAGE ON THE LEFT – USE AS IS, NO PURCHASE
Median survival
Carcinoid 43 months
pNET 27 months
Yao JC et al. J Clin Oncol. 2008;26:

20. Emerging Therapeutic Approaches
Somatostatin receptor
Peptide receptor radiotherapy
Angiogenesis
mTOR
mTOR = mammalian target of rapamycin

21. Targeting NETs Somatostatin receptors highly expressed by NETs
Targeting SST receptors can provide symptom and disease control
New targets could change treatment paradigm :
mTOR, PI3K, VEGF inhibitors
Other antiangiogenic agents
High potential for combinations
Use image as is
PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor

22. PROMID: Octreotide LAR Slows Progression in Midgut NETs
TTP in Midgut NET
Octreotide LAR vs placebo P =
HR = 0.34 [95% CI: 0.20–0.59]
Octreotide LAR (n = 42)
Median 14.3 months
Placebo: (n = 43)
Median 6.0 months
Time (months)
Proportion without progression
0.25
0.5
0.75 1 6 12 18 24 30 36 42 48 54 60 66 72 78
TO PURCHASE – USE AS IS
Is the capitalization of the expanded form of PROMID: Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors standard? (i.e. Capping Placebo, Octreotide, Randomized, MIDgut). [copyeditor note]
Yes—the capitalized letters are those that spell out the acronym (in addition to LAR, which is always capped.) [SD note]
Based on conservative ITT analysis
HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors; TTP = time to progression
Rinke A et al. J Clin Oncol. 2009;27:

23. Potential Management of Advanced NETs Post-PROMID
Functional
Octreotide LAR + chemotherapy
pNET
Nonfunctional
Chemotherapy
Investigational
agents
(No approved therapies
available)
Carcinoid syndrome
Octreotide LAR
Disease progression
Midgut No syndrome
Consider octreotide LAR
Carcinoid
No Standard
Non-midgut No syndrome
No standard

24. Peptide Receptor Radiotherapy (PRRT)
111In pentetreotide
DTPA-CO-NH-D-Phe-Cys S
Thr(ol)-Cys
Phe
D-Trp
Lys
Thr
111In
DOTA-CO-NH-D-Phe-Cys
Tyr
90Y DOTATOC
90Y
177Lu DOTATATE
Thr-Cys
177Lu
Systemic radiotherapy targeting somatostatin receptors
Compounds vary by isotope and carrier molecule
177Lu DOTATATE1 and 90Y DOTATOC2: promising results in phase 2 studies
Insert semicolon after 2001 in reference 2.
[done – SD]
177Lu-DOTATATE:177Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid0 (DOTA), Tyr3-octreotate; 90Y DOTATOC: [90Y-DOTA]-D-Phe1-Tyr3-octreotide.
1. Kwekkeboom DJ et al. J Clin Oncol. 2008;26: Waldherr C et al. Ann Oncol. 2001;12:

25. 90Y-DOTATOC, 90Y-Edotreotide
Multiple studies
Various doses: 6 GBq/m2, 7.4 GBq/m2, GBq/m2
Various schedules of 3-4 treatments
RRs from smaller studies: 23%1 & 24%2
RR from larger study (N = 90): 4.4%3
Semicolons are missing after 2001 and 2010 in references, and there’s an extra space after 43: in the first reference.
[done – SD]
Waldherr C et al. J Nucl Med. 2002;43:
Waldherr C et al. Ann Oncol. 2001;12:
Bushnell DL et al. J Clin Oncol. 2010;28:

26. 177Lu DOTATATE Phase 2 Study
N = 504
GBq in 4 cycles
Efficacy in 310 pts, NOT ITT
RR: 30%
Median TTP: 40 months
Does intent-to-treat need hyphens? [Yes – per SD]
Add colon after TTP in the last bullet point? [done –SD]
Missing graphics? [? Not sure what this means –SD]
ITT = intent-to-treat; RR = response rate; TTP = time to progression
Imaging studies property of James Yao, MD.
Kwekkeboom DJ et al. J Clin Oncol. 2008;26:

27. 177Lu DOTATATE: What Does It Mean?
If ITT principle applied to response:
91 responses among 504 patients
RR drops to 18%
High reported TTP calculated only for 249 who did not have PD as best treatment outcome
PRRT clearly active; strong need for rigorous phase 3 study
If ITT principle is applied to response (add ‘is’) ?
High reported TTP calculated only for the (add ‘the’)?
[note from SD: these changes not implemented b/c language is unambiguous as shown – this standard style is used to keep slide text brief]
PD = progressive disease
Kwekkeboom DJ et al. J Clin Oncol. 2008;26:

28. NET: Bevacizumab fCT Baseline Day 2 after bevacizumab
Move ‘MD’ up to same line as ‘Yao’
Imaging studies property of James Yao, MD. 28

29. Bevacizumab: Randomized Phase 2 Trial
Stable dose of octreotide
x 2 months
Random assignment
Bevacizumab + PEG interferon α-2b
(+ octreotide)
Protocol
starts here
Bevacizumab
PEG interferon α-2b
18 wks
ITT by assignment
Bevacizumab
(n = 22)
PEG interferon
PR (confirmed) 4 SD 17 16 PD 1 6
P = .019 (2-sided exact)
Additional responses:
1 pt with PD on PEG interferon had PR after addition of bevacizumab
1 pt with SD on PEG interferon had PR after addition of bevacizumab
delete space after 2008;
PR = partial response; SD = stable disease
Yao JC et al. J Clin Oncol. 2008;26: 29

30. Sunitinib: Phase 2 Open-Label Study
Carcinoid, n (%) (n = 41)
Islet cell, n (%) (n = 66)
All pts, n (%) (N = 107)
PR (confirmed)
1 (2)
11 (17)
12 (11) SD
34 (83)
45 (68)
78 (73) PD
5 (8)
6 (6)
Not evaluable
5 (12)
10 (9)
Kulke MH et al. J Clin Oncol. 2008;26:

31. Carcinoid: SWOG 0518 Phase 3 Study
Octreotide + interferon
Poor prognosis
(N = 283) R
Supported by CTSU
Endorsed by ECOG, CALGB, NCCTG
Added study # to title
Octreotide + bevacizumab
CALGB = Cancer and Leukemia Group B; CTSU = Cancer Trials Support Unit; ECOG = Eastern Oncology Cooperative Group; NCCTG = North Central Cancer Treatment Group; SWOG = Southwestern Oncology Group 31

32. Sunitinib Phase 3 pNET Study
Stopped early at unplanned time point
March 12, 2009
Sunitinib 37.5 mg
continuous dosing R
Islet cell w/PD over prior 12 months (340 planned,
171 accrued)
Placebo
Clarified PFS rates and added reference.
I’ve changed the word timepoint in the uber document; if those edits are accepted then the word should also be changed here. [SD note: made this change]
Investigator-reported PFS:
11.4 mo with sunitinib vs 5.5 mo with placebo
PFS = progression-free survival
Raymond E et al. ASCO GI 2010; Abstract 127.

33. mTOR Signaling Pathways
Receptor Tyrosine Kinase
Nutrients &
Metabolites
RAS
IRS-1
Grb
SOS
Protein Synthesis
Cyclin D, p27
Glut 1
VEGF, PDGF-β P
HIF-1α P P
PI3K
AKT
TSC1/2
Rheb
Everolimus
mTORC1
Use as is
Why ‘Receptor’ in bold?
p70S6K
4EBP1
eIF4E
Metabolism
Angiogenesis
Growth &
Proliferation

34. Subependymal giant-cell
astrocytoma
Islet cell carcinoma
Angiomyolipomas
Imaging studies property of James Yao, MD.

35. MDACC: Everolimus + Octreotide LAR Response
Per protocol
Overall N = 60
Carcinoid n = 30
Islet cell n = 30 PR
13 (22%)
5 (17%)
8 (27%) SD
42 (70%)
24 (80%)
18 (60%) PD
5 (8%)
1 (3%)
4 (13%)
PFS (median)
60 wks
63 wks
50 wks
ITT RR: 20%
MDACC = M. D. Anderson Cancer Center; RR = response rate
Yao JC et al. J Clin Oncol. 2008;26: 35

36. RADIANT-1: Study Design
Advanced pancreatic NET with RECIST progression following cytotoxic chemotherapy
Stratum 1: No octreotide LAR 60d before enrollment
Received everolimus 10 mg/d
Stratum 2: Octreotide LAR ≥ 3mo before enrollment
Received everolimus 10 mg/d + octreotide LAR ( ≤ 30 mg, q28d)
Stratum 1 n = 115
SCREEN
Stratum 2 n = 45
Everolimus +
octreotide LAR
Everolimus
Primary endpoint
RR stratum 1
Secondary endpoints
RR stratum 2
Response duration
Safety
PFS
Survival PK
Why capping of all words in expanded form of RECIST? [SD note: Because those words spell out the acronym « RECIST »]
Lowercase ‘e’ in ‘Primary endpoint’ and ‘Secondary endpoints’?
Little horizontal line to the right of word ‘SCREEN’ overlaps vertical line slightly
Treatment until progression; CT or MRI at baseline & q3mo
PK = pharmacokinetics; RECIST = Response Evaluation Criteria In Solid Tumors
Yao JC et al. J Clin Oncol. 2010;28:69-76.

37. RADIANT-1: Best Change from Baseline Central Radiology Review
Stratum 1: Everolimus
(n = 115)
Central radiology
ITT, n (%) PR
11 (9.6) SD
78 (67.8)
Clinical benefit
(PR + SD)
89 (77.4) PD
16 (13.9)
Unknown
10 (8.7)
Stratum 2: Everolimus + Octreotide LAR
(n = 45)
Lowercase ‘f’ in ‘From’ in the title of this slide
Central radiology
ITT, n (%) PR
2 (4.4) SD
36 (80.0)
Clinical benefit
(PR + SD)
38 (84.4) PD
0 (0.0)
Unknown
7 (15.6)
Yao JC et al. J Clin Oncol. 2010;28:69-76.

38. RADIANT-1 PFS by Central Review
Everolimus
Everolimus + octreotide LAR
100
100 80
n = 115 80
n = 45 60
Probability (%)
Probability (%) 60 40 40 20 20
Median PFS = 16.7 mo
Median PFS = 9.7 mo
TO PURCHASE BOTH IMAGES – USE AS IS 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 26
Time, mo
Time, mo
Patients at risk
Patients at risk
115
111 81 58 54 36 25 15 12 5 3 3 1 45 39 32 22 21 19 14 10 8 3 3 1
Yao JC et al. J Clin Oncol. 2010;28:69-76. 38

39. Pivotal Phase 3 Trials with Everolimus in NETs
Accrual completed
Octreotide LAR + Everolimus
Advanced carcinoid with syndrome in progression
(N = 429) R
Octreotide LAR + placebo
Accrual completed
Lowercase w in with in title of slide
What does the superscript 1 in placebo refer to? Is a footnote to this slide missing?
Best supportive care + everolimus*
Advanced pNET in progression
(N = 410) R
Best supportive care + placebo*
*Octreotide LAR included as best supportive care. 39 39

40. Conclusions NETs not that rare Progress being made
Somatostatin analogs effective in controlling hormonal syndrome
PROMID suggests octreotide LAR controls tumor growth in midgut carcinoids
Phase 2: VEGF and mTOR inhibitors have single-agent activity in NETs
Confirmatory phase 3 studies ongoing